Preimplantation genetic diagnosis for Zellweger syndrome

I., Barsky; S., Rechitsky; T., Sharapova; T., Linnik; O., Verlinsky; A., Kuliev; Y., Verlinsky
April 2008
Reproductive BioMedicine Online (Reproductive Healthcare Limited;Apr2008 Supplement 3, Vol. 16, pS-29
Academic Journal
Introduction: Zellweger syndrome is an autosomally recessive hereditary disease characterized by the absence of peroxisomes in liver and kidneys. The disorder is caused by mutations in one of the peroxisome biogenesis (PEX) genes. At least 23 PEX genes have been reported to be essential for peroxisome biogenesis in various species. The absence of peroxisomes leads to impairment of many metabolic pathways, especially beta-oxidation of very long chain fatty acids (VLCFA). The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, developmental delay and neonatal lethality. The frequency of this condition is estimated to be 1 in 50,000. Materials/Methods: Four PGD cycles were performed for three couples. Each couple had previously experienced a birth of a child affected by Zellweger syndrome who deceased shortly thereafter. Two couples were reported to be carriers for the mutations in PEX1 gene. Paternal mutation was identified as lbp insertion (c.2097insT) in exon 13 in the first couple; maternal mutation was not detected. Two different mutations were found in the second couple; one of them was paternal splicing mutation IVS 18 +1 A-G and the other maternal missense mutation R798G. Both parents in the third couple were carriers for R119X mutation in the PEX2 gene. PGD was performed on polar bodies (PB) and blastomeres. Nested and hemi-nested multiplex PCR protocol was used for the above mutations and linked short tandem repeats (STR). Protocol for the PEX1 gene included the following polymorphic markers: D7S1509, D7S1813, D7S1789, D7S646, D7S629 and D7S558. Protocol for the PEX2 gene included D8S 1105, D8S 1126, DSS 1805, D8S 1134, D8S1829, D8S2245 and D8S541 tightly linked STR. Ensuing PCR, mutations and linked markers were analysed by restriction endonuclease digestion and fluorescent fragment analysis. Results: In four IVF cycles, 21 pairs of PB and 31 embryos were tested according to the optimized multiplex PCR protocol. From these PGD cycles, 21 embryos were found to be unaffected and suitable for transfer. Seven of them were transferred, resulting in three pregnancies. Prenatal and post-natal diagnoses confirmed the accuracy of PGD for Zellweger syndrome. Six healthy children were born, of which two were normal and four unaffected carriers of the mutations.


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